By Vibhu Sharma, MD, MS

Assistant Professor of Medicine, University of Colorado, Denver

Dr. Sharma reports no financial relationships relevant to this field of study.

SYNOPSIS: This was a multicenter, blinded, parallel-group, randomized trial of mechanically ventilated critically ill patients. Achieving 100% calorie requirements did not change outcomes at six months when compared to a more modest goal of 70% of predicted calorie requirements.

SOURCE: Deane AM, Little L, Belloma R, et al. Outcomes six months after delivering 100% or 70% of enteral calorie requirements during critical illness (TARGET). A randomized controlled trial. Am J Respir Crit Care Med 2020;201:814-822.

Mechanically ventilated patients were randomized to a calorie-dense formula (1.5 kcal/mL) targeted to deliver 100% of calories or routine enteral nutrition (1 kcal/mL) targeted to deliver approximately 70% of calories. While the delivered protein content of these formulations was identical (~ 5.5 g/dL), the delivered carbohydrate and fat contents of the calorie-dense formulation were higher. The target rate for each group was 1 mL/kilogram of ideal body weight per hour. The target rate was to be achieved in 48 hours and, to minimize the chance of overfeeding, a rate of feed greater than 100 mL/hour was not exceeded. Trial feeds were continued for 28 days or until enteral nutrition was discontinued.

Most patients (73%) were critically ill in a medical critical care setting, a minority were elective surgical patients (10%), and the rest were emergency surgical patients (17%). Patients were excluded if enteral feeds were deemed contraindicated or death was deemed inevitable. The primary endpoint for this analysis was mortality six months after initial randomization, with the hypothesis that administration of 100% of calorie requirements would improve mortality after initial admission to the intensive care unit (ICU) with a critical illness.

Secondary outcomes were functional scores and quality of life measured using the EuroQOL questionnaire verbally administered to surviving participants (or surrogates) by phone using a visual analog scale (VAS) at day 180 from randomization.

Investigators administering these questionnaires were blinded to the initial treatment allocation. The EuroQOL questionnaire is a five-dimension, five-level questionnaire that measures mobility, personal care activities, usual activities, pain/discomfort, and anxiety/depression and can be adapted to country-specific value sets. Since there is no country-specific set for Australia/New Zealand, the authors used index values adjusted to value sets for England/Canada. Each of the health domains is divided into five levels of response. The investigators dichotomized responses to each domain into “problems” (level 2-5) and no problems (level 1). Additionally, participants in the study were categorized into five groups based on premorbid age and functional status (< 65 years old/working, < 65 years/not working, ≥ 65 years/living at home with family, ≥ 65 years/living in a long-term facility). The World Health Organization Disability Assessment Schedule (WHODAS) was used to assess the disability for those individuals not working after discharge. Disability was rated as “none or mild” or “moderate to severe” based on the WHODAS score.

The study was adequately powered (3,774 patients were recruited). Statistical analyses included median differences between groups for relevant outcomes and relative risks using log binomial regression. Sensitivity analyses were conducted for major outcomes (e.g., mortality) and functional outcomes using the worst value for each score for patients who died prior to assessment at 180 days. All but 43 patients (recruited but did not receive study intervention, withdrew consent to continue, or withdrew consent to use data) in the cohort were included in an intention-to-treat analysis.

All domains were evaluable in 2,492 patients (65.3%) of the original cohort. The rest died or could not complete a visual analog score. The baseline characteristics of the calorie-dense and routine enteral nutrition groups were similar. Individuals randomized to the calorie-dense group received substantially more calories (mean group difference 605 kcal/d). Despite increased energy delivery during critical illness to one of two well-matched groups, mortality was not different. Additional calories did not affect functional outcomes or the proportion of individuals with either mild or moderate to severe disability. Additional calories also did not affect rates of return to work, hours worked, or changes in work done after recovery from critical illness among those < 65 years of age and living independently after recovery. There were also no differences between groups when stratified by age. The authors concluded that “six months after randomization … increasing calorie delivery during critical illness to approximately 100% of recommended intake did not affect any ... outcomes.”

COMMENTARY

The results of this study add to a series of conclusions from recent trials that calorie-dense feeding does not change outcomes for the critically ill. The EDEN (Initial Trophic versus Full Enteral Feeding in Patients with Acute Lung Injury) trial1 assessed the effect of trophic feeds for the first six days vs. full feeds on outcomes in the setting of acute lung injury. No differences in mortality or ventilator-free days were found.

Although it is clear that critical illness affects quality of life after discharge, the results of the TARGET trial suggest that high calorie feeds in particular do not affect either mortality or quality of life among survivors at six months after discharge. Importantly, protein requirements were met at 100% for both groups of patients and, therefore, it is clear that the lack of protein in the diet administered was not a confounding factor. However, the authors noted that international guidelines typically recommend greater amounts of protein to be delivered in the critically ill. There was no signal of harm from providing 100% of calories in any subgroup.

The TARGET study has a few limitations. First, given the small proportion of patients undergoing elective surgery (~ 10% in each group), extrapolation of the results of this study to this subset of surgical patients is difficult. Second, none of the patients were morbidly obese (body mass index [BMI] > 30); these patients may have specific nutritional needs that are not captured by this study. Third, most patients had cardiovascular or respiratory diagnoses, but only 9% in each group had sepsis. Fourth, there is no explicit statement about the racial mix of patients. Fifth, since the EuroQOL instrument has not been adapted to patients in Australia and New Zealand, the investigators used index values adjusted to value sets for England and Canada. Finally, I am unable to explain how a visual analog scale to calculate EuroQOL was administered to individuals over the phone.

Given the disappointing results of targeting 100% of caloric requirements with respect to six-month outcomes, what is an intensivist to do with respect to feeds in the critically ill? Previously, the ANZICS group has published in-hospital outcomes related to the delivery of energy-dense vs. routine enteral nutrition in the critically ill.2 Higher calorie delivery did not affect survival time, infective complications, receipt of organ support, or ICU-free survival either. Outside of scenarios of patients in shock on multiple vasopressors where feeds are probably not indicated, “use the gut” is the most relevant recommendation. It is very likely ideal to begin trophic feeds as soon as feasible with titration up as tolerated. It may not be important to deliver 100% of calories, but it is likely important to deliver 100% of the protein requirement. While frequently the target is to deliver “tube feeds at goal,” most patients never reach this target. That is probably OK as long as protein delivery goals are in line with international recommendations.

Involving a trained nutritionist/dietitian with expertise in delivery of critical care nutrition as a part of the critical care team is important to allow for nuanced delivery in scenarios such as the severely malnourished, the morbidly obese, when tube feeds are contraindicated, or when total parenteral nutrition is indicated. 

REFERENCES

  1. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: The EDEN randomized trial. JAMA 2012;307:795-803.
  2. TARGET Investigators, for the ANZICS Clinical Trials Group; Chapman M, Peake SL, Bellomo R, et al. Energy-dense versus routine enteral nutrition in the critically ill. N Engl J Med 2018;379:1823-1834.